Skin permeation device for analyte sensing or transdermal drug delivery

ABSTRACT

Devices, systems, kits and methods for increasing the skin&#39;s permeability controlled by measured skin electrical parameter are described herein. They may be used for transdermal drug delivery and/or analyte extraction or measurement. The controlled abrasion device contains (i) a hand piece, (ii) an abrasive tip, (iii) a feedback control mechanism, (iv) two or more electrodes, and (v) an electrical motor. The feedback control mechanism may be an internal feedback control mechanism or an external feedback control. The kit contains the controlled abrasion-device, one or more abrasive tips, optionally with a wetting fluid. The method for increasing the skin&#39;s permeability requires applying the controlled abrasion device to a portion of the skin&#39;s surface for a short period of time, until the desired level of permeability is reached. Then the abrasion device is removed, and a drug delivery composition or device or an analyte sensor is applied to the treated site.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Ser. No. 60/914,552, entitled“Device for Permeabilizing Skin for Analyte Sensing or Transdermal DrugDelivery”, filed Apr. 27, 2007, the disclosure of which is incorporatedby reference.

FIELD OF THE INVENTION

The present invention is directed to the field of devices and methodsfor transdermal analyte sensing or drug delivery.

BACKGROUND OF THE INVENTION

In general, permeation of drugs through the skin occurs at a very slowrate, if at all. The primary rate limiting step in this process is thepassage of compounds through the outermost layer of skin, called thestratum corneum. The stratum corneum is a thin layer of dead cells thatacts as an impermeable layer to matter on either side of this layer. Thestratum corneum primarily provides the skin's barrier function. It haslong been recognized that loss or alteration of the stratum corneumresults in increased permeability to many substances; materials can moreeasily diffuse into or out of the skin. The barrier function of the skinpresents a very significant problem to pharmaceutical manufacturersinterested in transdermal administration of drugs or in cutaneouscollection of bodily fluids.

Transmission and reception of electrical signals and biologicalmaterials through human skin is also hindered by the stratum corneum.For example, signal fidelity of bioelectrical potentials and currentsmeasured through skin are degraded by the high impedance of the stratumcorneum. Accordingly, the high impedance presents a problem to receivingthrough the skin the ideal transmission and measurement of bioelectricalsignals from human cells, organs, and tissues.

Removal of the stratum corneum reduces the high impedance of the skinand allows better transmission and reception of electrical signals orbiological species into and from human tissues. It has also beendemonstrated that electromagnetic energy induced alterations of thestratum corneum result in increased permeability to substances (see e.g.U.S. Pat. No. 6,315,722 to Yaegashi, U.S. Pat. No. 6,251,100 to Flock etal., U.S. Pat. No. 6,056,738 to Marchitto et al., and U.S. Pat. No.5,643,252 to Waner et al.). Alternatively, compounds commonly referredto as “permeation enhancers” can be used, with some success, topenetrate the stratum corneum. Traditional approaches require theabrasion of skin with sand paper and brushes, the stripping of skin withtape and toxic chemicals, the removal of stratum corneum by laser orthermal ablation, or the puncturing of skin with needles. Preparation ofskin by these methods may be highly variable, hazardous, painful to thesubject, and are generally inconvenient.

Conventional approaches for skin preparation for drug delivery orextraction of analytes through the skin require external feedbackmechanism to control the extent of skin preparation. In practice, anelectrically conductive coupling medium, a return electrode and/or ahydrogel patch are generally needed to enable the feedback mechanism forcontrolled skin preparation (see e.g. U.S. Publication No. 20060100567to Marchitto et al. and U.S. Publication No. 20030204329 to Marchitto etal.). The reliability of such devices and systems can be questionablesince the return electrode can provide accurate feedback only whenlocated on a skin site which has sufficient electrical conductivity.Unfortunately, conductivity of the skin varies by a variety ofconditions, such as age, location, sun exposure, use of lotions,moisture level, and ambient conditions, etc.

Therefore, an improved system for reducing the high impedance of theskin is needed.

It is an object of the invention to provide an improved system forreducing the high impedance of the skin.

It is a further object of the invention to provide an improved methodfor measuring the impedance of the skin.

It is yet a further object to provide an improved transdermal drugdelivery and/or analyte sensing system.

SUMMARY OF THE INVENTION

Devices, systems, kits and methods for increasing the skin'spermeability are described herein. They may be used for transdermal drugdelivery and/or analyte extraction and measurement. The controlledabrasion device contains (i) a hand piece, (ii) an abrasive tip, (iii) afeedback control mechanism, (iv) two or more electrodes, and (v) anelectrical motor. Preferably the feedback control mechanism is aninternal feedback control. In this embodiment, the abrasive tip containstwo electrodes, i.e. both the source electrode and the return electrode.In another embodiment, the feedback control mechanism is an externalfeedback control. In the preferred embodiment for external feedbackcontrol, the device contains a co-axial or concentric arrangement of thetwo electrodes. In this embodiment, the abrasive tip contains the sourceelectrode and the return electrode is located at the proximal end of thehand piece. The abrasive tip can be made of any material with a surfacethat can abrade skin. The material can be conductive or non-conductive.In the preferred embodiment, the material is a conductive material.Optionally, the abrasive tip is wetted with a wetting fluid prior toapplication on the skin. The controlled abrasion device may be providedin a kit, where the kit contains the device, one or more abrasive tips,and, optionally, a wetting fluid. In one embodiment, the abrasive tip ismoistened with the wetting fluid and sealed in a container to retain thewetting fluid in the tip. In another embodiment, the wetting fluid issupplied in a separate container or in a material, such as a prepackagedwipe. The method for increasing the skin's permeability includesapplying the controlled abrasion device to a portion of the skin'ssurface for a short period of time, such as for up to 30 seconds. Thedesired level of skin impedance or conductance, and thus the resultingpermeability of the treated site, can be set at a predetermined value.

Alternatively, the level of skin impedance or conductance can beselected based on the desired level of skin integrity, the subject'ssensation of discomfort, or the duration of the application. The devicecontains a feedback circuit as part of the feedback control mechanism,which uses an appropriate algorithm or signal processing based on theconductivity information to determine when the desired level of skinpermeability has been reached. Once the desired level of permeabilityhas been reached, the abrasion device is removed and either a drugdelivery composition or device or an analyte sensor is applied to thetreated site.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is shows an exemplary controlled abrasion device using anexternal feedback control mechanism.

FIGS. 2A and 2B are illustrations of an abrasive tip containing twoelectrodes for an internal feedback control. FIG. 2A contains a frontview and an exploded view of the abrasive tip shown relative to anabrasion device, and FIG. 2B is a side view of the abrasive tip, shownin contact with the skin surface.

FIGS. 3A-D are illustrations of a controlled abrasion device usingexternal feedback control mechanism. FIG. 3A is a cross-sectional viewof the controlled abrasion device, which illustrates the current paththrough the skin and into the device. FIGS. 3B and 3C are bottom planviews of the proximal end of the controlled abrasion device thatillustrate a co-axial or concentric arrangement of the two electrodes.FIG. 3B illustrates an abrasive tip that also serves as the sourceelectrode. FIG. 3C illustrates an abrasive tip in which a conductiveelement is inserted therein, where the conductive element serves as thesource electrode. FIG. 3D is a cross-sectional view of the proximal endof a disposable abrasive tip, which illustrates the contact of thesource electrode with a spring that provides a conductive path from theabrasive tip to the motor shaft.

FIG. 4 is a flowchart of a method for controlling abrasion of an area onthe surface of the skin to achieve the desired level of permeability.

FIG. 5 is a graph of the time variation of skin conductivity (I, in theunit of Counts) during application of a controlled abrasion device tothe skin. The solid line is a graph of counts, (1 Count=0.0125 μ-Amps)over time (Seconds) (solid line); the dashed line is a graph of thefirst derivative of the conductivity curve, i.e. ΔI/ΔT (Count/Second)over time (Seconds); the horizontal dotted lines represent the maxima inthe first derivative.

FIG. 6 is a flowchart depicting a method of determining when toterminate the permeation step.

FIGS. 7A, B, and C are representative graphs that correspond with thesteps in the flowchart of FIG. 6.

FIG. 8 is a graph of blood glucose level (mg/dL) versus time (hours) ofthe results obtained using the abrasion system on a test subject topermeate the skin, followed by continuous transdermal glucosemonitoring.

DETAILED DESCRIPTION OF THE INVENTION

The devices, systems, kits and methods described herein provide aconvenient, rapid, economic, and minimally invasive system and methodfor increasing the skin's permeability. These devices, systems, kits andmethods may be used for transdermal drug delivery and/or analytemeasurement.

I. Controlled Abrasion Device

A controlled abrasion device (10) is illustrated in FIG. 1. The devicecontains (i) a hand piece (12), (ii) an abrasive tip (20), (iii) afeedback control mechanism (30), (iv) two or more electrodes (40), and(v) an electrical motor (50). The devices may contain additionalcontrols and/or a user interface.

The devices illustrated in FIGS. 1 and 3A-D have external feedbackcontrol mechanisms. Preferably the feedback control mechanism is aninternal feedback control mechanism. An exemplary controlled abrasiondevice with an internal feedback control mechanism is illustrated inFIG. 2A.

a. Abrasive Tip

The abrasive tip (20) may be reusable or disposable. If the abrasive tipis reusable, it is designed to be cleaned between uses and reused. In apreferred embodiment, the abrasive tip is disposable.

A disposable abrasive tip is attachable to and removable from theproximal end of the hand piece by any suitable connecting means.

A preferred embodiment of the disposable abrasive tip is illustrated inFIGS. 3A and 3D. In a preferred embodiment, the disposable abrasive tipis attached to a tube (24), preferably a plastic tube. The tube (24) isinserted into a central void in a plastic cup or cone (27), where thecentral void is shaped to receive the tube while allowing the tip tomove when the device is turned on (see FIG. 3D). The cup or cone (24) isdesigned to prevent fluids from contacting the hand piece (12), therebyminimizing or eliminating cleaning of the hand piece after use. In thepreferred embodiment, the opening (25) of the cup or cone (24) fitsinside the outer wall (21) of the proximal end (14) of the hand piece(12) (see FIG. 3D). In the preferred embodiment the outer wall (21)contains a conductive material that serves as the return electrode (44).

i. Materials

The abrasive tip can be made of any material with a surface that canabrade skin, such as sand paper, rough textiles, such as dermal gradefabrics that are used in cosmetic microdermabrasion, typically made from100% medical grade nylon and have a plurality of coatings and finishes,wire brushes, carbon fibers, or microneedles. The material can beconductive or non-conductive. For example, white aluminum oxide, anon-conductive material, is readily available at low cost in medicalgrade. This material is able to withstand elevated temperatures, such asthose typically present in any vitrification process that may benecessary for high volume binding/fabrication to produce the abrasivetip. In some embodiments, a softer material than aluminum oxide ispreferred so that the material is less irritating to the skin thanaluminum oxide. Polymeric beads may be used as the abrasive material inplace of aluminum oxide. Generally the polymeric beads provide a softer,less irritating material than aluminum oxide. Material preference isbased on the particular individual to be treated and the purpose of thetreatment. Thus for different individuals, different materials may besubstituted for the above-listed materials.

With proper engineering designs, it is possible that conductivematerials can also be used as the abrasive material in the abrasive tip.Suitable conductive materials include, but are not limited to, metals,carbon, conductive polymers and conductive elastomers.

In a preferred embodiment, the material is a conductive material,preferably a metal, most preferably stainless steel sheet metal, withmultiple holes or perforations (22A and B). An example of thisembodiment is illustrated in FIG. 3B. The abrasive tip may be formed bypunching the material to form a disc with a diameter that correspondswith the area of the skin to be abraded. The disc then shaped into adome and attached to a tube (24), preferably a plastic tube.

ii. Dimensions

The abrasive tip can have any suitable thickness and diameter. In oneembodiment, abrasive particles are coated onto a plastic base, such asacrylonitrile butadiene styrene (ABS), and the thickness of the abrasivecoating is defined by the grit size of the abrasive particles. In apreferred embodiment, the abrasive particles have a grit size of about120 (approximately 0.0044 inches in diameter, or about 120 microns).Typically, the grit size will be 120 or lower as particles with gritsizes larger than 120 have been shown to cause bruising.

Typically the abrasive tip will have a thickness ranging from 0.5microns to 150 microns, preferably ranging from 15 microns to 120microns.

The tip can have any suitable shape or geometry. Typically the tip has across-sectional area in the shape of a circle. The size of the tipdepends on the size of the area to be permeabilized by abrasion. Forexample, for applications requiring a small area to be permeabilized,the abrasive tip can have a diameter of up to several micrometers, suchas from 1 to 25 micrometers. For applications requiring largerpermeabilized areas, the abrasive tip can have a diameter of up toseveral inches, such as from 0.1 to 5 inches.

iii. Wetting Fluid

Depending on the electrical conductivity of the abrasive tip material, awetting fluid may or may not be needed to wet the abrasive tip andthereby provide a conductive path to the skin. The wetting fluid maycontain any suitable agent, such as water, salts, ionic or non-ionicsurfactants, preservatives, alcohol, glycerol, gel, and other similaragents. Various mixtures of these agents may be formulated into wettingfluids with various conductivity levels, depending on the desiredapplication. As used herein a “highly conductive fluid” or a “fluid witha high conductivity” refers to a fluid with a conductivity from about1,000 to about 100,000 μSiemens/cm. As used herein a “fluid with a lowconductivity” refers to a fluid with a conductivity from about 0.1 toabout 999 μSiemens/cm. For example, for the external feedback controlmechanism, as described in FIG. 1, if the abrasive tip is made ofnon-conductive material, such as plastic or gritted materials, a highlyconductive fluid is needed to provide a conductive path through theskin. If the abrasive tip is made of a conductive material, such asmetal, a wetting fluid with either a high conductivity or one with a lowconductivity may be used. Alternatively, the system may require nowetting fluid, such as if the metallic abrasive tip itself issufficiently conductive to provide a conductive path through thepermeated skin. In a preferred embodiment, a wetting fluid with aconductivity of 500 to 50,000 μSiemens/cm is used with the externalfeedback control mechanism.

For the internal feedback control mechanism as described in FIGS. 2A and2B, a wetting fluid with a low conductivity should be used. Wettingfluids with high conductivities should generally be avoided as they arelikely to cause a short circuit and improper device function. Theabrasive tip illustrated in FIGS. 2A and 2B is typically formed of anon-conductive material. The use of such a wetting fluid provides a lowconductivity baseline when the skin is intact, followed by a significantincrease in conductivity when the skin site is permeated with theabrasion device.

Preferably the wetting fluid contains water, salts, alcohol, glycerol,non-ionic surfactants, preservatives, polyethylene glycol, and/ormixtures thereof. An example of wetting fluid with a high conductivitycontains 0.1-20% (wt/wt) of salts, 0-2% (wt/wt) ionic surfactants, 0-20%(wt/wt) alcohol and 0-1% (wt/wt) preservative in purified water. Anexample of wetting fluid with a low conductivity contains 0-2% non-ionicsurfactants, 0-50% alcohol and 0-1% preservative in purified water.

Optionally, the wetting fluid contains one or more active agents, suchas a drug, diagnostic agent or prophylactic agent, to be delivered tothe subject. Such a wetting fluid is particularly useful in drugdelivery applications.

In one embodiment, the abrasive tip is formed from a non-conductivematerial and the wetting fluid is a fluid with a low conductivity.

iv. Electrodes

The abrasive tip (20) typically contains a first electrode (42) (alsoreferred to herein as the “source electrode”) in electrical contact at asite of interest on the tissue to be permeated and in electricalcommunication with the motor (50) to provide continuity with thefeedback control circuitry. In one preferred embodiment, the abrasivetip either contains a conductive element that serves as a sourceelectrode or is formed of a conductive material (see FIG. 3D), whichserves as a source electrode, and the source electrode is in contactwith a spring (28) to provide continuity from the abrasive tip (20) tothe motor shaft. Although FIG. 3D illustrates the use of an abrasive tipthat also serves as the source electrode, the same spring configurationcan be used with an abrasive tip formed of a non-conductive materialthat contains at least one conductive element inserted therein. In thisembodiment, the source electrode is located within the abrasive tip (20)in a position level with the outer surface of the abrasive tip.

The same spring configuration illustrated in FIG. 3D can be used with adevice containing an internal control feedback mechanism, such as thedevice depicted in FIG. 2A.

In some embodiments of the abrasion device that contain an externalfeedback control mechanism, the abrasive tip does not contain anelectrode. In these embodiments, the first electrode (42) (or sourceelectrode) may be located in a locating ring (60) (see e.g. FIG. 1).

The electrode can be made of any suitable conducting material including,for example, metals and conducting polymers. Additionally bothelectrodes can be designed with any suitable shape that allows theelectrodes to contact the skin and electrically communicate with thefeedback control circuitry.

Multiple electrodes can be used to achieve more homogeneous skinpermeation. To provide accurate electrical reading, the surface of thepatient's skin in contact with at least one electrode must besufficiently permeated, i.e. the stratum corneum should be removed fromthe site where the electrode is applied.

In a preferred embodiment, the abrasive tip (20) is designed with aninternal feedback control mechanism. In this embodiment, the abrasivetip contains two electrodes, which are located within the abrasive tipin a position leveled with the outer surface of the abrasive tip. Inthis embodiment, the abrasive tip contains both the first, or source,electrode (42) and the second, or return, electrode (44). The electrodesare made of any suitable conducting material including, for example,metals and conducting polymers. For the internal feedback mechanism tofunction properly in this embodiment, the abrasive tip is preferablyformed from a non-conductive material. If a wetting fluid is applied tothe abrasive tip, the wetting fluid is preferably a fluid with a lowconductivity.

In a preferred embodiment for a device with an external feedback controlmechanism, the proximal end (14) of the abrasion device (10) containstwo electrodes in a co-axial or concentric arrangement (see FIGS. 3B and3C). In this embodiment, the proximal end (14) of the abrasion device(10) contains both the first, or source, electrode (42) and the second,or return, electrode (44). Looking at a plan view of the proximal end(14) of the abrasion device, the source electrode is located in thecenter of the proximal end of the abrasion device. The source electrodeis surrounded by a space filled with air (26), which is surrounded bythe return electrode (44). FIG. 3B illustrates an embodiment where theabrasive tip is formed of a conductive material and also serves as asource electrode. FIG. 3C illustrates an embodiment where the abrasivetip is formed of a non-conductive material, and the source electrode,typically in the form of a wire, is inserted in the abrasive material.

In the coaxial or concentric arrangement, the second, or returnelectrode (44) is located in a the outer wall (21) of the proximal end(14) of the hand piece. Looking at a plan view of the proximal end (14)of the abrasion device, the return electrode (44) forms the outer ringof the device (see FIGS. 3B and 3C).

In another embodiment for a device with an external feedback controlmechanism, the second, or return, electrode (44) is separated from thecontrolled abrasion device (see e.g. FIG. 1). The location of the secondelectrode may be adjacent to or distant from the location of the firstelectrode.

b. Feedback Control Mechanism

The feedback control mechanism (30) involves the use of (i) a firstelectrode (42) located at the site of the skin that will be/is beingabraded (herein the “site of skin abrasion”) to measure periodically orcontinuously the skin's electrical conductance at the site of skinabrasion, (ii) at least a second electrode (44), which may be located ata site distant from the site of skin abrasion, may be adjacent to thesite of skin abrasion or may be in contact with the site of skinabrasion, and (iii) a controller (32). The controller performsmathematical analysis using an appropriate algorithm or signalprocessing on the conductivity information provided by the electrodes(42 and 44) and calculates the kinetics of the skin conductance. Thecontroller also controls the abrasion device (10).

The dynamic change in the conductance through the skin is measured inreal time while the abrasion device is applied to the skin. Signalprocessing is performed based on the measurement, and the level of skinpermeation is controlled by performing a dynamic mathematical analysis.The result of such analysis is used to control the application of theabrasion device to achieve the desired level of skin impedance. Thedesired level of skin impedance can be set at a predetermined value.Alternatively, the level of skin impedance can be selected based on thedesired level of skin integrity, the subjects sensation of discomfort,or the duration of the application.

An example of real time algorithm for controlled skin permeation isdescribed in U.S. Pat. No. 6,887,239 to Elstrom et al., and isdemonstrated in FIGS. 4-7. U.S. Pat. No. 6,887,239 to Elstrom et al.describes a general method for controlling the permeability of the skinsurface when a site is undergoing a permeation enhancement treatment.

FIG. 4 is a flowchart of a method for controlling abrasion of an area onthe surface of the skin to achieve the desired level of permeability.The skin permeation device referenced in step 108 is the abrasion devicedescribed herein. However, alternative permeation devices and methodsmay be modified to use the controlled feedback mechanism describedherein. Alternative permeation methods include tape stripping, rubbing,sanding, abrasion, laser ablation, radio frequency (RF) ablation,chemicals, sonophoresis, iontophoresis, electroporation, and thermalablation. In step 102, a first, or source, electrode is coupled inelectrical contact with a first area of skin where permeation isdesired.

Next, in step 104, a second, or return, electrode is coupled inelectrical contact with a second area of skin. This second area of skinmay be located at a site distant from the site of skin abrasion, may beadjacent to the site of skin abrasion or may be within the site of skinabrasion.

When the two electrodes are properly positioned, in step 106, an initialconductivity between the two electrodes is measured. This may beaccomplished by applying an electrical signal to the area of skinthrough the electrodes. In one embodiment, the electrical signal mayhave sufficient intensity so that the electrical parameter of the skincan be measured, but have a suitably low intensity so that theelectrical signal does not cause permanent damage to the skin, or anyother detrimental effects. In one embodiment, an AC source of frequencybetween 10 to 100 Hz is used to create a voltage differential betweenthe source electrode and the return electrode. The voltage suppliedshould not exceed 500 mV, and preferably not exceed 100 mV, or therewill be a risk of damaging the skin. The current magnitude may also besuitably limited. The initial conductivity measurement is made after thesource has been applied using appropriate circuitry. In anotherembodiment, a resistive sensor is used to measure the impedance of thearea of skin at a frequency between 10 and 100 Hz. In anotherembodiment, dual or multiple measurements with dual or multiple ACsource of frequency may be made using similar or dissimilar stimuli. Inanother embodiment, a 1 kHz source is used. Sources of other frequenciesare also possible.

In step 108, the abrasion device is applied to the skin at the firstsite.

In step 110, the conductivity between the two electrodes is measured.The conductivity may be measured periodically, or it may be measuredcontinuously. The monitoring measurements are made using the sameelectrode set up that was used to make the initial conductivitymeasurement.

In step 112, mathematical analysis and/or signal processing may beperformed on the time-variance of skin conductance data. Skinconductivity can be measured at set time periods, such as once everysecond during permeation treatment, or continuously.

After plotting the conductance data, the graph resembles a sigmoidalcurve, which can be represented by the following general sigmoidal curveequation (Eq. 1):C=C _(i)+(C _(f) −C _(i))/(1+e ^(−S(t-t*)))  Eq. 1

where C is current; C_(i) is current at t=0; C_(f) is the final current;S is a sensitivity constant; t* is the exposure time required to achievean inflection point; and t is the time of exposure.

FIG. 5 contains a representative set of data in the form of a plot ofcurrent over time. FIG. 5 demonstrates the time variation data of skinconductance while being treated with the abrasion device. In FIG. 5, theconductivity (Current Count, the solid line) was measured continuouslyduring a skin permeation procedure on a test subject.

The value of t* in Equation 1 corresponds to the exposure time requiredto achieve an inflection point (i.e., a point where the slope of thecurve changes sign), and corresponds with the peak of the firstderivative, which has a value of 625 based on the data represented inFIG. 4.

FIG. 6 is a flowchart depicting a method of determining when toterminate the permeation step. FIGS. 7A, B, and C are representativegraphs that correspond with the steps in the flowchart of FIG. 6. InFIG. 6, step 302, an A/D conversion is performed on the conductivitydata. This results in a graph similar to the one depicted in FIG. 7A.Next, in step 304, filtering is performed on the digital data. As shownin FIG. 7B, the filtered data has a smoother curve than the unfiltereddata of FIG. 7A. Next, in step 306, the slope of the curve iscalculated. In step 308, the maximum value for the slope is saved. Ifthe current value for the slope obtained during subsequent measurementsis greater than the maximum value that is saved, the maximum value isreplaced with the current value. Next, in step 310, if the slope is notless than or equal to the maximum value, the process returns to step 302to wait for a peak. If the slope is less than or equal to the maximumvalue, in step 312 the process detects a peak, or point of inflection,marked as “X” in FIG. 7C, then, in step 314, the device terminates theapplication of abrasive force to the skin.

In one embodiment, the detection of the peak may be validated. Thisadditional step may be provided to ensure that the “peak” detected instep 312 was not mere noise, but was actually a peak.

In other embodiments, the abrasive force may continue to be applied evenafter the inflection point, i.e. “peak”, is reached. In anotherembodiment, the abrasive force is applied until the slope decreases to acertain value. Referring to FIG. 5, after the inflection point isreached, the slope decreases as the abrasive force is applied (seedashed line). Thus, the abrasive force may continue to be applied untilthe slope decreases by a preset percentage of the maximum of the firstderivative of the conductivity curve, such as 50%, or to a predeterminedvalue. As above, this determination is flexible and may vary fromindividual to individual. Similarly, as shown in FIG. 5, a real time,first derivative of the conductivity curve was calculated (step 306 ofFIG. 6) and the maximum was found to be 625 (steps 308 and 312). Theoffset (i.e. baseline) for this curve was about 17 (ΔI/ΔT). For the datarepresented in FIG. 5, if the stopping point for the permeation step ispreset at 50% of the maximum of the first derivative of the conductivitycurve, the instrument will shut off automatically when the firstderivative value reaches 321 (data corrected for offset), indicatingthat the skin permeation is complete. Other percentages may be used, andthe percentage may be based on factors including pain threshold and skincharacteristics.

In another embodiment, the stopping point is set to a predeterminedperiod of time. This predetermined period of time may be based on apercentage of the time to reach the inflection point. For example, oncethe inflection point is reached, the abrasion device continues to beapplied for an additional 50% of the time it took to reach theinflection point (see e.g. FIG. 5). Thus, if it took 14 seconds to reachthe inflection point, abrasion is applied for an additional 7 seconds(not shown in figure). Other percentages may be used, and the percentagemay be based on factors including pain threshold and skincharacteristics.

In another embodiment, the current at the inflection point is measured,and then application of the abrasive tip is continued for a presetpercentage of this current. For example, if the inflection point isreached at 40 μamps, and the abrasive tip is continued for a presentpercentage of the current at the inflection point, such as 10% of thecurrent at the inflection point, the abrasive tip will be applied untila total of 44 μamps of current is reached. Again, this determination isflexible and may vary from individual to individual.

Referring to FIG. 4, in step 114, the parameters describing the kineticsof skin impedance (or conductance) changes are calculated. Theseparameters include, inter alia, skin impedance, the variation of skinimpedance with time, initial skin impedance, moving average of skinimpedance, maximum skin impedance, minimum skin impedance, anymathematical calculation of skin impedance, final skin impedance, skinimpedance at inflection time, current count, final current, exposuretime to achieve the inflection time, etc.

In step 116, the skin permeation device applied in step 108 isterminated when desired values of the parameters describing skinconductance are achieved.

c. Electrical Motor

An electrical motor (50) is located in the hand piece (12). The abrasivetip (20) connects directly or indirectly with the motor (50), whichallows the motor to move, such as by oscillation or rotation, theabrasive tip, when the controlled abrasion device is turned on.

Electrical motors are available in two primary classes: AC and DCmotors. They are either rotary or linear.

Preferably the motor (50) is a rotary, DC motor. In a preferredembodiment, the motor is a rotary, brushed, DC motor due to its relativeease of use with standard power supplies (i.e. direct current batteries)as compared to “brushless” motors that utilize more expensive rare earthmetals in their construction, and availability. However, brushlessmotors may also be used with the device.

The motor can produce a variety of motion patterns, such as linear,vibration, concentric, co-axle, and off-axle motions. Additionally, themotor can produce a variety of motion speeds, such as ranging from0.01-10,000 rps or Hz.

d. Means for Providing Force to the Abrasive Tip

In the preferred embodiment, the controlled abrasion device contains oneor more means for providing a force to the abrasive tip to ensure thatthe abrasive tip remains in contact with the skin when the controlledabrasion device is turned on. Suitable means include a spring (16)loaded motor shaft or coupler to provide a downward (i.e. towards theskin surface) force on the abrasive tip when it is in contact with theskin surface (see FIG. 3A).

As shown in FIG. 3A, the spring (16) contracts when the abrasive tip ispressed against the skin. When the spring contracts, the proximal end(14) of the hand piece (12) moves towards the surface of the skin,causing the return electrode (44) to contact the skin. Thus, in thisposition, the source electrode (42), the abrasive tip (20) and thereturn electrode (44) are in contact with the skin's surface.

e. Return Electrode

As noted above, the device typically contains at least one secondelectrode, which serves as a return electrode (44) (see e.g. FIGS. 1, 2A2B, and 3A-D). For devices designed to contain an internal feedbackcontrol mechanism, the return electrode is located in the abrasive tip(see FIGS. 2A and 2B). However, if the device is designed to contain anexternal feedback control mechanism, the return electrode is placed at asite on the skin surface that is different from the site of skinabrasion (see FIG. 1 and FIGS. 3A-C). The return electrode may be placedat a site on the skin that is distant from the site of skin abrasion(see e.g. FIG. 1) Alternatively the return electrode may be placed at asite on the skin that is adjacent to the site of skin abrasion (see e.g.FIG. 3A-C). As shown in FIG. 1, the return electrode (44) is inelectrical contact with the controller, and is in electrical contactwith the first electrode (42). As shown in FIG. 3A, the return electrode(44) may be integrated in the device. The return electrode (44) is inelectrical contact with the controller, and is in electrical contactwith the first electrode (42).

The reliability of such devices with a return electrode that is at asite distant from the site to be permeated can be questionable since thereturn electrode can provide accurate feedback only when it is locatedon a skin site which has sufficient electrical conductivity. Thus, inthe preferred embodiment, the return electrode is located on theabrasive tip. In this embodiment, the return electrode is also incontact with the skin to be permeated.

In a preferred embodiment for the external feedback control mechanism,the return electrode (44) in the coaxial or concentric arrangement withthe first electrode. In this embodiment, the second, or return electrode(44) is located in a the outer wall (21) of the proximal end (14) of thehand piece and forms a outer ring surrounding the source electrode andabrasive tip (see FIGS. 3B and 3C). Moving outward from the center ofthe device, the abrasive tip and source electrode are surrounded by aplastic tube (24) to which the abrasive tip is attached, the plastictube is surrounded by a void or space filled with air (26), the void issurrounded by a plastic cup or cone (27), which is surrounded by aconductive material that serves as the return electrode (44).

II. System for Analyte Sensing

The controlled abrasion device described herein can be combined with ananalyte sensor to detect the level of one or more analytes of interestpresent in a body fluid. The body fluid may be extracted by physicalforces, chemical forces, biological forces, vacuum pressure, electricalforces, osmotic forces, diffusion forces, electromagnetic forces,ultrasound forces, cavitation forces, mechanical forces, thermal forces,capillary forces, fluid circulation across the skin, electro-acousticforces, magnetic forces, magneto-hydrodynamic forces, acoustic forces,convective dispersion, photo acoustic forces, by rinsing body fluid offskin, and any combination thereof. The body fluid may be collected by acollection method including absorption, adsorption, phase separation,mechanical, electrical, chemically induced, and a combination thereof.The presence of an analyte may be sensed by a sensing method includingelectrochemical, optical, acoustical, biological, enzymatic technology,and combinations thereof.

For example, after using the controlled abrasion device to achieve thedesired level of permeability at a skin site, an analyte sensor, such asa glucose sensor device, may be placed over the skin site that has beentreated by the abrasion system. The glucose sensor functions byreceiving glucose flux continuously through the skin. In response, thedevice provides an electrical signal, in nanoamperes (nA), which iscalibrated to the reference blood glucose (BG) value of the subjectusing a commercial finger-sticks glucose meter. The combination of thecontrolled abrasion system with a blood glucose sensor is describedbelow in the examples.

Although the above example refers to glucose sensing, other analytes canbe analyzed using the same method. The analyte may be any molecule orbiological species that is present in a biological fluid, such as blood,plasma, serum or interstitial fluid. The analyte to be monitored can beany analyte of interest including, but not limited to glucose, lactate,blood gases (e.g. carbon dioxide or oxygen), blood pH, electrolytes,ammonia, proteins, biomarkers or any other biological species that ispresent in a biological fluid.

III. System for Drug Delivery

The controlled abrasion device described herein can be combined with adrug delivery composition or device to transdermally deliver drug to asubject. The drug may be any suitable therapeutic, prophylactic, ordiagnostic molecule or agent, in any suitable form. The drug may bedissolved or suspended in a liquid, solid, semi-solid, or encapsulatedand/or distributed in or within micro or nanoparticles, emulsion,liposomes, or lipid vesicles. Drug delivery may occur into blood, lymph,interstitial fluid, cells, tissues, and/or organs, or any combinationthereof. The drug is typically delivered systemically.

For example, after using the controlled abrasion device to achieve thedesired level of permeability at a skin site, drug delivery compositionor device, such as an ointment, cream, gel or patch containing the drugto be administered, may be placed over the skin site that has beentreated by the abrasion system.

Alternatively, the drug may be included in a wetting fluid that isapplied to the abrasive tip. In this embodiment, the drug may beadministered simultaneously as the surface is being abraded.

IV. Kits

Kits for controlled abrasion include the abrasion device described aboveand one or more abrasive tips. Optionally, the kit includes a wettingfluid, which is packaged in an appropriate container, to be added to theabrasive tip. In another embodiment, the wetting fluid is pre-applied tothe one or more abrasive tips and which are packaged to maintain themoisture in the abrasive tip. In yet another embodiment, the kitincludes one or more pre-moistened wipe containing the wetting fluid.

If the device utilizes disposable abrasion tips, the kit preferably alsocontains one or more disposable plastic cups or cones (27). Preferablythe disposable abrasive tip is attached to a tube (24) that is designedto mate with and connect to the hand piece.

If the abrasion device is designed to contain an external feedbackcontrol mechanism, the kit also includes one or more return electrodes.

V. Methods of Reducing Skin Impedance

A. Controlled Abrasion Device

The controlled abrasion device described herein can be applied to thesurface of a subject's skin to reduce the skin impedance by 30 times ormore compared to the skin impedance measured following wetting with purewater in the absence of a skin permeation treatment. Typical skinimpedance measurements following wetting with pure water in the absenceof a skin permeation treatment are about 300 k-ohms or above, whenmeasured by placing two electrodes within a distance of approximately 1cm on the wetted skin. Following treatment of the same area of the skinusing the controlled abrasion device, the impedance value can be reducedto about 10 k-ohms or lower.

The abrasive tip is typically applied for a short period of time for upto 90 seconds, such as from 1 to 30 seconds, preferably from 5 to 25seconds. The desired level of skin impedance (or conductance), and thusthe resulting permeability of the treated site, can be set at apredetermined value. Alternatively, the level of skin impedance (orconductance) can be selected based on the desired level of skinintegrity, the subject's sensation of discomfort, or the duration of theapplication, as described above.

Once the desired level of permeability has been reached, the abrasiondevice is removed and either a drug delivery composition or device or ananalyte sensor is applied to the treated site. Drug delivery can proceedimmediately, as soon as the drug delivery system is applied to theabraded skin. In a similar manner, the analyte can diffuse from the bodyand into the analyte sensor as soon as the analyte sensor is applied tothe skin. However, accurate values of the analyte are usually notavailable during the “warm-up” period, i.e. the time it takes for thetransdermal analyte flux to reach equilibration, the sensor to consumeskin-borne analyte and possibly other interference species, and thephysical coupling of sensor to the skin sites to become stable. Thewarm-up period typically lasts for about 1 hour following application ofthe analyte sensor to the prepared site.

Following application of the abrasion device, the site typically remainspermeable for up to 24 hrs, and in some embodiment for up to 72 hrs.

B. Other Permeation Devices

Other permeation devices and techniques may be used in place of thecontrolled abrasion device described herein to achieve a desired levelof skin permeation. For example, the feedback control mechanism can becombined with other skin preparation methods, such as tape stripping,rubbing, sanding, abrasion, laser ablation, radio frequency (RF)ablation, chemicals, sonophoresis, iontophoresis, electroporation, andthermal ablation.

EXAMPLES Example 1 Comparison of Two Skin Permeation Methods:Sonophoresis and Abrasion

In a 6-subject, 24-hour study the performance of the abrasion method wascompared to a sonophoresis method described in U.S. Pat. No. 6,887,239to Elstrom et al. using the same control algorithm as indicated in FIG.4. Each subject had one abraded site and one sonicated site on chest orabdomen sites.

For the controlled abrasion system, the abrasion device described inFIG. 1 was applied to the patients' skin for 5 to 25 seconds, until theconductivity feedback threshold was attained (as described previously insection I.b. Feedback Control Mechanism).

For the controlled sonophoresis system, ultrasound at a frequency of 55kHz was applied to the patients' skin for 5 to 30 seconds using theSontra SonoPrep® ultrasonic skin permeation device. The ultrasound wasapplied until the conductivity feedback threshold was attained (asdescribed previously in section I.b. Feedback Control Mechanism).

Glucose sensor units were placed on each of the two target skin sitesprepared by controlled abrasion or sonophoresis. Throughout the courseof the study, reference finger-stick blood glucose (“BG”) samples weretaken during the waking hours, at hourly intervals, or at 15-minuteintervals near meal times, and were correlated to the electrical signalof the sensor.

Analysis of this correlation provides information about device accuracy,consistency and effective length of performance.

FIG. 8 is a graph of the results obtained using the abrasion system on atest subject to permeate the skin followed by continuous transdermalglucose sensing. Table 1 shows the results of the direct comparison ofabrasion to sonication as the means of skin permeation for continuousglucose monitoring. Table 1 shows the average values based on the dataobtained from six subjects.

TABLE 1 Statistical Results Lag 12 hr 24 hr 24 hr Baseline Time MARDDrift MARD % A Technique n (nA) (min) 1 cal (%) 2-3 cal Region Abrasion6 395 14 18.4 31 11.7 85 Ultrasound 6 409 10 16.2 26 13.1 80

The reference blood glucose (Ref BG) values were measured by acommercial blood glucose meter using finger sticks. Two calibrationswere done to the glucose sensor based on Ref BG values at 1.2 and 9.1hours (labeled as “calibration points” on FIG. 8). The close proximityof the sensor glucose reading (Predicted BG) to the reference bloodglucose (Ref BG) indicates good accuracy of the transdermal glucosesensor. The 24-hour Mean Absolute Relative Difference (MARD) between theRef BG and the Predicted BG was 11.9 mg/dl.

For permeation using the controlled abrasion device, the average 24-hrMARD was 11.7 mg/dl with a signal drift of 31%. For the controlledsonophoresis system, the average 24-hr MARD was 13.1 mg/dl with a signaldrift of 26%. Thus the controlled abrasion device provided tracking (nAto BG correlation) that was comparable to or in some cases better thanthe sonophoresis system, in terms of warm-up period (one hour), accuracy(MARD, Mean Absolute Relative Difference, between sensor predictedglucose and reference BG, in the unit of mg/dl), and drift(time-dependent % deviation of sensor glucose and reference BG), andpercentage of data distribution in the “A region” based on Clarke ErrorGrid analysis (“% A Region”).

Example 2 Lowering Impedance of Skin Following Application of AbrasionDevice

When human skin is wetted by pure water, the impedance value is usually300 k-ohms or above, when measured by placing two electrodes within adistance of approximately 1 cm on the wetted skin. However, when thesame area was treated by with a controlled abrasion device using acontrol algorithm as shown in FIG. 1, by placing the device on the skinsurface for 5 to 25 seconds and obtaining the impedance valuesimultaneously with the application of the device, the impedance valuewas significantly reduce to about 10 k-ohms or lower. In this study, theabrasive tip contained white aluminum oxide (120 grit) coated onto anABS base.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1. A controlled abrasion device comprising a hand piece, an abrasivetip, a feedback control mechanism, and an electrical motor, wherein theabrasive tip does not contain a micro-needle, wherein the feedbackcontrol mechanism comprises (a) a source electrode, (b) a returnelectrode and (c) a controller, wherein the source electrode is locatedin the abrasive tip, wherein the return electrode is located at theproximal end of the hand piece, wherein the abrasive tip connectsdirectly or indirectly to the motor such that the motor is able to causethe abrasive tip to move, and wherein the abrasive tip is attachable toand removable from the proximal end of the hand piece, and wherein thesource electrode and the return electrode are in electricalcommunication with the controller, and wherein the feedback controlmechanism measures the conductance through the skin in real time andcalculates in real time the rate of change in the conductance over timewhen the device is applied to the skin to control the level of skinabrasion.
 2. The device of claim 1, wherein the feedback controlmechanism is an internal feedback control mechanism.
 3. The device ofclaim 1, wherein the abrasive tip comprises a wetting fluid.
 4. Thedevice of claim 1, wherein the abrasive tip comprises a materialselected from the group consisting of conductive and non-conductivematerials.
 5. The device of claim 4, wherein the abrasive tip comprisesa conductive material, and wherein the abrasive tip is the sourceelectrode.
 6. The device of claim 5, wherein the conductive materialcomprises perforations.
 7. The device of claim 5, wherein an outer wallof the proximal end of the hand piece comprises the return electrode. 8.The device of claim 1, wherein the abrasive tip is a disposable abrasivetip, and wherein the device further comprises a cup that surrounds theabrasive tip.
 9. The controlled abrasion device of claim 1, wherein thereturn electrode surrounds the abrasive tip.
 10. The controlled abrasiondevice of claim 9, wherein the abrasive tip comprises a wetting fluid.11. The device of claim 1, wherein the electrical motor is a rotary,direct current (DC) motor.
 12. The device of claim 1, further comprisinga spring loaded motor shaft that provides a downward force on theabrasive tip, when the abrasive tip is in contact with the skin surface.13. A method for reducing the impedance of a tissue site comprisingapplying an abrasive tip of a controlled abrasion device to the tissuesite, wherein the device comprises a hand piece, the abrasive tip, afeedback control mechanism, and an electrical motor, wherein thefeedback control mechanism comprises (a) a source electrode, (b) areturn electrode and (c) a controller, wherein the source electrode islocated in the abrasive tip, and wherein the return electrode is locatedat the proximal end of the hand piece, wherein the abrasive tip connectsdirectly or indirectly to the motor such that the motor is able to causethe abrasive tip to move, wherein the abrasive tip is attachable to andremovable from the proximal end of the hand piece, and wherein theabrasive tip does not contain a micro-needle, wherein the sourceelectrode and the return electrode are in electrical communication withthe controller, and wherein the feedback control mechanism measures theconductance through the skin in real time and calculates in real timethe rate of change in the conductance over time when the device isapplied to the skin to control the level of skin abrasion, turning theelectrical motor on, and measuring an electrical parameter of the tissuesite.
 14. The method of claim 13, wherein the step of measuring anelectrical parameter of the tissue site comprises applying an electricalcurrent between the source electrode and the return electrode.
 15. Themethod of claim 13, wherein the electrical parameter is selected fromthe group consisting of current count change during a specified timeperiod, instantaneous rate of current count change, impedance valuechange at the tissue site during a specified time period, and differenceof impedance values between the tissue site and a reference tissue site.16. The method of claim 13, wherein the feedback control mechanism is aninternal feedback control mechanism.
 17. The method of claim 16, whereinthe return electrode is located in an outer wall of the proximal end ofthe hand piece.
 18. The method of claim 13, further comprising the stepsof analyzing the electrical parameter, and controlling one or more ofthe duration, speed, or force of the abrasive tip based on results ofthe analyzing step.
 19. The method of claim 18, wherein the step ofanalyzing the electrical parameter comprises processing the measuredelectrical parameter to derive a current count or impedance value of thetissue site.
 20. The method of claim 18, wherein the step of controllingcomprises turning off the motor when the analyzed electrical parameteris equal to or exceeds a predetermined value.
 21. The method of claim20, further comprising the steps of removing the abrasive tip from thetissue site, and thereafter placing an analyte sensor or drug deliverycomposition or device on the tissue site.
 22. The method of claim 21,wherein the analyte sensor is capable of sensing an analyte selectedfrom the group consisting of glucose, lactate, blood gases, blood pH,electrolytes, ammonia, proteins and biomarkers.
 23. The method of claim13, wherein the step of measuring an electrical parameter of the tissuesite is performed continuously during the step of applying the abrasivetip to the tissue site.
 24. A kit for reducing the impedance of a tissuesite comprising a controlled abrasion device and at least one abrasivetip, wherein the abrasion device comprises a hand piece, a feedbackcontrol mechanism, and an electrical motor, wherein the feedback controlmechanism comprises (a) a source electrode, (b) a return electrode and(c) a controller, wherein the return electrode is located at theproximal end of the hand piece, wherein the abrasive tip connectsdirectly or indirectly to the motor such that the motor is able to causethe abrasive tip to move, and wherein the abrasive tip is attachable toand removable from the proximal end of the hand piece, and wherein thesource electrode and the return electrode are in electricalcommunication with the controller, and wherein the feedback controlmechanism measures the conductance through the skin in real time andcalculates in real time the rate of change in the conductance over timewhen the device is applied to the skin to control the level of skinabrasion, and wherein the abrasive tip comprises an abrasive materialand the source electrode, and wherein the abrasive tip does not containa micro-needle.
 25. The kit of claim 24, wherein the abrasive tipcomprises a wetting fluid.
 26. The kit of claim 24, further comprising awetting fluid.